Ranolazine (Ranexa®)
The mechanism of action of ranolazine is not well understood. It is thought to act by improving relaxation of the myocardium, reducing stiffness of the left ventricle and improving perfusion of the myocardium.
Myocardial ischaemia interferes with the action of the myocardial sodium channels. This results in increased levels of intracellular calcium and reduced myocardial relaxation during diastole. Increased myocardial stiffness increases myocardial oxygen consumption exacerbating ischaemia.
The contraction of cardiac muscle is mediated by an action potential triggered by inward movement of sodium and calcium ions. Increased intracellular sodium leads to increased levels of calcium ions. Increasing intracellular calcium triggers myocardial muscle contraction.
Ranolazine acts by inhibiting the late opening of the sodium channels which reduces intracellular sodium levels and restores calcium levels more rapidly. This restoration of calcium levels results in more rapid relaxation of the myocardium. Myocardial relaxation reduces oxygen consumption and allows increased perfusion of the heart muscle during diastole.
Ranolazine does not cause changes in heart rate, blood pressure or vasodilation. This makes ranolazine a particularly useful treatment option for angina patients who also suffer with hypotension or bradycardia. It is also a useful first line treatment option where other antianginal drugs are contra-indicated or not tolerated.
The recommended starting dose for ranolazine is 375mg twice a day titrated to 500mg twice daily after two to four weeks according to the patient's response. The dose can be further increased if necessary to a maximum dose of 750mg twice daily.
The dose may need to be reduced if patients experience side effects including dizziness, nausea or vomiting. Treatment should be discontinued where a reduction in dosage does not resolve these adverse effects.
Ranolazine is primarily metabolised by CYP3A4. Administration of inhibitors of CYP3A4 with ranolazine has been shown to increase plasma ranolazine levels. Examples of potent CYP3A4 inhibitors include ketoconazole, itraconazole, HIV protease inhibitors, clarithromycin, telithromycin and grapefruit juice. The manufacturers of Ranexa® contra-indicate co-administration with potent CYP3A4 inhibitors.
In addition ranolazine has a mild inhibitory effect on CYP3A4 which must be taken into account when prescribing drugs metabolised by CYP3A4.10 Simvastatin clearance is dependent on CYP3A4 and concomitant use with ranolazine has been associated with increased levels of simvastatin. All patients prescribed ranolazine and simvastatin should be counselled on the signs of myopathy.